A. Field On The Invention
The present invention relates generally to methods and compositions for measuring glucose tolerance, such as in connection with oral glucose tolerance tests for the diagnosis of diabetes mellitus and other conditions relating to the body's response to serum glucose levels. In more particular aspects, the invention relates to an improved method for diagnosing diabetes mellitus which includes the use of a potable beverage containing a relatively low molar concentration and total loading dose of glucose.
B. Description Of Related Art
Diabetes mellitus is a disease characterized by hyperglycemia occurring from a relative or absolute decrease in insulin secretion decreased insulin sensitivity or insulin resistance. The morbidity and mortality of this disease result from vascular, renal, and neurological complications.
An oral glucose tolerance test is a clinical test used to diagnose diabetes. In an oral glucose tolerance test, a patient's physiological response to a glucose load or challenge is evaluated. Generally, in an adult patient about 2 grams of glucose is administered for each kilogram of body weight, in children the amount is relatively less, being about 1.75 grams per kilogram body weight. The glucose load is administered to the patient as a potable concentrated solution of glucose in water. Reported glucose concentrations range generally from about 25% to about 50% (W/V) (3). Currently more than 10 "standard" oral glucose tolerance tests, each with its own method of administration and interpretation, are in use.
After ingesting the glucose, the patient's physiological response to the glucose challenge is evaluated. Generally, this is accomplished by determining the patient's blood glucose levels (the concentration of glucose in the patient's plasma, serum or whole blood) for several predetermined points in time. Several statistical methods have been developed to analyze the blood glucose data obtained, e.g., the Wilkerson point method.
Clinicians have long known that the conditions under which an oral glucose tolerance test is administered will affect the data obtained. In an effort to improve reliability and standardize oral glucose tolerance testing, the Committee on Statistics of the American Diabetes Association (ADA) has recommended standardized conditions under which the tests should be performed. These conditions include that the patient be in good health, maintain a minimum intake of 150 grams of dietary carbohydrates for three days, and fast for at least eight hours, but no longer than sixteen hours, prior to testing. Further, on the day of the test the patient should not smoke, use drugs or exercise, and should avoid undue mental stress. Presently, most oral glucose tolerance tests are administered following a similar protocol. However, even when conditions are closely monitored, oral glucose tolerance tests have yielded inaccurate, and non-reproducible data. Because of the inaccuracy of the test, patients are frequently misdiagnosed as diabetic.
Although they are commonly used throughout the world, oral glucose tolerance tests have been criticized as inaccurate. One published study concluded that patients subjected to repeated oral glucose tolerance tests showed a blood glucose mean difference of 26mg/dl at 1 hour and 20mg/dl at 2 hours. Clinicians, because of results such as these, have proposed that the use of oral glucose tolerance tests be discontinued, suggesting that less harm might be caused by not using the test than by misdiagnosing diabetes with it.
Studies conducted by the present inventors indicate that the glucose concentration of the test solution, the volume of the test solution, and the total dose of glucose administered, all affect patient comfort, test accuracy, and reproducibility of results. Significantly, these are the parameters which vary the most from one clinical group to another. For example, the dose of glucose recommended by the National Institutes of Health (NIH) work group is 75 gm for adults, and 1.75 gm/kg body weight for children, up to about a maximum of 75 gm. According to NIH, NIH chose this amount since a 50 gram glucose dose, previously recommended by the British Diabetic Association, was insufficiently provocative to demonstrate glucose intolerance, whereas a 100 gram glucose dose, recommended by the American Diabetic Association, was associated with symptoms of nausea and vomiting during the test (6).
As discussed above, the glucose dose is generally administered as an aqueous solution. The rate and efficiency of gastrointestinal glucose absorption, and the comfort of the patient being evaluated, depend to a great extent on the concentration (osmolarity) of the glucose solution administered. Researchers have reported that highly concentrated glucose solutions, e.g., 25-50% (W/V), cause gastric irritation, and a delay in gastric emptying time resulting in nausea and vomiting. It is believed that these adverse effects are caused by a gastrointestinal osmotic imbalance (2). This imbalance leads to a disturbance in gastrointestinal glucose absorption which can result nausea and vomiting, and in delayed or incomplete glucose absorption.
Results of a survey of 10 hospitals in the San Antonio, Texas area conducted by the present inventors revealed that when a glucose solution including varying amounts of glucose (75 gm or 100 gm) was administered to adult patients, as required in the standard oral glucose tolerance test, nausea and vomiting were reported in 40-80% of the patients. Of the hospitals surveyed nausea and vomiting was reported in nearly 100% of the pregnant patients-the worst symptoms were seen with "cola" flavored beverages. Researchers have reported that low concentration glucose solutions, e.g., 5-15% necessitate the administration of large volumes of liquid, which, in turn, causes nausea and vomiting, as well as poor gastrointestinal absorption (2).
The data obtained from oral glucose tolerance tests (OGTTs) is used to diagnose diabetes in a patient. However, many different glucose methodologies, i.e., glucose loading dose, solution volume, and glucose concentration, have been utilized in administering oral glucose tolerance tests. These different methodologies result in significant changes in patient comfort and in blood glucose values. This results in confusion in the interpretation of oral glucose tolerance tests. Presently, the oral glucose tolerance test is of questionable value because of the variability of the response in patients. Indeed, several clinicians recommend that the oral glucose tolerance test be abandoned (5).
Although different versions of the oral glucose tolerance test have been in use for almost 200 years, physicians are still unable to identify and classify diabetes with certainty in many individuals. Current oral glucose tolerance tests have numerous documented pitfalls and irregularities with both patient compliance and diagnostic acumen. The problems of the current tests include, but are not limited to, nausea, vomiting, nonreproducible results, and misdiagnosis. Thus, the present invention is generally directed to providing a method for diagnosing diabetes in a human subject which avoids the problems of currently available oral glucose tolerance tests.
Accordingly, there is presently a need for a well-tolerated oral glucose tolerance test which does not cause the nausea and vomiting typically associated with currently available tests. Further, there is a need for an oral glucose tolerance test that will more accurately diagnose diabetes. Lastly, there is also a need for an oral glucose tolerance test which yields consistent, reproducible results.